Direct DNA inoculation has been shown to induce broad immune responses against HIV-1, including humoral immunity, specific helper cell responses as well as specific CTL responses. It is our hypothesis that intermittent HIV antigen-specific stimulation of the compromised immune system will benefit the HIV infected patient by partially reconsitituting immune competence. We intend to stimulate the immune response in HIV-infected patients by administering multiple intramuscular injections of viral protein-producing DNA plaslmid(s). A total of 4 clinical trials are planned, beginning with phase I trials which are primarily intended to investigate the safety of the intramuscular DNA plasmid technique and of the individual plasmids at several dose levels in asymptomatic, HIV-infected individuals (Trials #1, #2 land #3). The first trial using the HIV-1 gag/pol plasmid will be initiated after safety and possibly immunogenicity are established in the SIV model but the goal is to start this trial within the first year of the program. The second and third studies will follow and will be essentially the same design as the first trial with modifications as needed to address safety or immunogenicity issues that arise. The research plan has been designed to move forward, narrowing the investigative focus to allow manageable trial sizes and efficient evaluations into phase I/II study of the 2 most promising plasmids or plasmid combinations at the 2 most effective doses as determined by the earlier phase I trials. By the end of the grant period, patients with HIV- related disease will have access to these experimental therapies in the context of Trial #4. The long-term goal of the proposed research is to move this promising new therapeutic approach into and through initial phase I clinical trials and to enter preliminary efficacy phase I/II trials with the most promising plasmid(s) by the end of the 4-year grant period.